1. Description of the problem

Sinusoidal obstructive syndrome (SOS), initially called veno-occlusive disease (VOD), is a frequent complication of SCT associated with the use of high-dose chemotherapy and radiation. It results in hepatomegaly, fluid retention and ascites, and cholestasis.

Although most patients recover from SOS, almost all patients with severe disease will die from disease-related complications. Although several disease interventions can be attempted, the most important management strategy is meticulous fluid and electrolyte balance.

SOS is a clinical syndrome of 1) hepatomegaly, often with right upper quadrant tenderness; 2) fluid retention and weight gain, often with severe edema and ascites; and 3) hyperbilirubinemia and jaundice.

Key management points

The most important therapeutic measure is meticulous management of fluid balance. Fluid retention and weight gain are common findings and are hallmarks of this syndrome due to capillary leak and third spacing and often patients are intravascularly volume depleted. Overly aggressive diuresis and paracentesis can exacerbate volume depletion and precipitate renal failure. Important supportive care measures include:

1. Careful and frequent assessment of fluid balance with exam, daily weights, and other measurements to ensure adequate intravascular volume

2. Diuresis if needed, with caution

3. Discontinue and avoid any medications that may cause hepatotoxicity or renal toxicity if possible.

4. Drainage of ascites or pleural effusions for comfort or to improve respiratory status and function

5. Opioids may be needed to control liver pain in some cases.

6. Hemofiltration or dialysis to control volume excess and renal failure

2. Emergency Management

The most important aspects of emergency management are to (1) discontinue potential liver and renal toxins, (2) ensure the diagnosis is correct, and (3) provide very close and careful fluid and electrolyte balance. In the case of respiratory failure associated with severe ascites and pleural effusions, drainage may be more effective than diuresis.

Dopamine or other agents may be used to ensure renal perfusion in the setting of profound intravascular volume depletion. Since SOS may be reversible, ventilator support may be necessary for management until prognosis is better defined.

3. Diagnosis

SOS typically develops within the first 3 weeks of HSCT. SOS/VOD is a clinical diagnosis typically manifested by the otherwise unexplained occurrence of 1) hepatomegaly with possible right upper quadrant pain; 2) weight gain >5% from baseline, often with edema and ascites; and 3) hyperbilirubinemia (>2) and jaundice.

The modified Seattle criteria require presentation before day 20 after HSCT with 2 or more of the following: Bilirubin >/= 2 mg/dl; hepatomegaly/right upper quadrant pain; ascites with or without unexplained weight gain >2% from baseline.

The Baltimore criteria require a bilirubin >/= 2 mg/dl before day 21 of HSCT with at least 2 of the following: hepatomegaly (usually painful); ascites; weight gain>5% over baseline.

There are no laboratory tests specific for SOS despite numerous studies attempting to identify biochemical correlates. Some studies suggest serum markers of fiber and deposition or hypercoagulability may correlate with development of SOS/VOD.

Imaging tests may support the diagnosis but are not diagnostic.

Ultrasound and MRI may show hepatomegaly, ascites, and slow hepatic venous flow without biliary dilatation, slow or reversed portal vein flow, obstruction, or infiltration to otherwise explained hepatomegaly and cholestasis. These findings are more common later in the course of the disease and are most useful to rule out other causes in the differential diagnosis.

Transvenous liver biopsy with measurement of hepatic venous wedge pressure is the gold standard for diagnosis of SOS, though it may be associated with morbidity in critically ill patients, particularly with severe thrombocytopenia in the midst of their SCT. A biopsy is important when the diagnosis is uncertain but may not be necessary.

The hepatic venous pressure gradient of more than 10 mm Hg is specific for SOS. Histology typically shows disruption of sinusoidal endothelium, sinusoidal fibrosis, hepatocyte necrosis and extravasation of red cells through the space of Disse.

How do I know this is what the patient has?

SOS is a clinical diagnosis made when a patient meets clinical criteria described above.

When there is doubt about the diagnosis a transvenous liver biopsy is indicated, if feasible.

Differential diagnosis

SOS is a clinical diagnosis unless a liver biopsy is feasible and indicated. The most common conditions in the differential diagnosis include:

1) GVHD (not usually associated with hepatomegaly and weight gain/fluid retention. GVHD also often occurs later, though hyperacute GVHD can occur around the same time as SOS.

2) Hepatic vein obstruction (Budd-Chiari syndrome). This can be diagnosed with vascular imaging.

3) Sepsis (in particular when requiring large volumes of fluid resuscitation leading to fluid retention and weight gain). This is not usually associated with hepatomegaly and right upper quadrant pain but needs to be ruled out appropriately.

4) Cholestatic liver disease from medications, infections, obstruction or other causes. Examination of all medications (particularly azole anti-fungal therapies) is important. Infections and obstruction should be ruled out with appropriate serologic testing, cultures, and imaging studies.

5) Congestive heart failure. This can present with weight gain, fluid retention, and cholestasis. A detailed cardiac evaluation is important to rule this out and to help with fluid balance management.

6) Tumor infiltration of the liver. This would be very unusual early after transplant and typically would not be associated with fluid retention/weight gain. Imaging studies or biopsies may be needed if this is of concern.

4. Specific Treatment

Supportive care

This is the mainstay of care for SOS:

1. Diurese cautiously for symptom control, but not at the expense of intravascular volume.

2. Perform paracentesis or thoracentesis if ascites or effusions are causing difficulty breathing or severe discomfort. This may be more effective than diuresis.

3. In patients with AKI, hemofiltration or hemodialysis may be required to control volume

4. Avoid hepatic and nephrotoxic drugs.

Possible therapeutic interventions

1. Thrombolytic therapy. TPA and heparin have been used in small numbers of patients and may be effective in <30% of cases; however, there is a high risk of fatal cerebral and pulmonary hemorrhage.

2. Transjugular intrahepatic portosystemic shunt (TIPS). This may result in symptomatic improvement by reducing portal

pressure and decreasing ascites but does not treat the underlying pathology.

3. Defibrotide: Defibrotide is a single-stranded polydeoxyribonucleotide with anti-thrombotic and thrombolytic properties that does not appear to increase the risk of bleeding. Approximately 50% of patients with severe SOS showed resolution. This drug is not FDA approved in the United States and as of 2010 was available only on specific clinical trials.

4. Consider liver transplantation in a patient whose prognosis is limited by SOS and has recovered from the acute toxicity of transplant.

5. Numerous other medical therapies have been tried with anecdotal successes. These include intravenous N-acetylcysteine, prostaglandin E1, prednisone, vitamin E and glutamine. Infusion of antithrombin III and activated protein C has not been of benefit.

5. Disease monitoring, follow-up and disposition

SOS requires careful monitoring of fluid balance to maintain adequate INTRAVASCULAR volume. Occasionally this may require invasive monitoring since third space accumulation of fluid (edema, ascites, effusions) is common and does not reflect volume status. Body weight, fluid status, liver function and renal function should be monitored daily. Avoidance of hepatotoxins and adjustment of medication dosing for liver dysfunction is necessary. SOS can resolve with no long-term sequelae.

Pathophysiology

SOS usually occurs in the first few weeks after high-dose conditioning therapy. It is felt to result from direct injury to the sinusoidal endothelial cells and hepatocytes. This explains why it is more common after myeloablative allogeneic transplant when compared to reduced intensity conditioning and transplant.

Injury typically occurs in the zone 3 hepatic acinus. It is common to see increases in a number of biomarkers that reflect endothelial injury. These include elevations in thrombomodulin, soluble tissue factor and plasminogen activator inhibitor.

Commonly accepted risk factors for SOS include high-dose conditioning therapy, methotrexate as GVHD prophylaxis, older age, prior lung dysfunction, poor performance status, extensive prior therapy, liver dysfunction prior to transplant and the use of an HLA mismatched donor graft. Prior abdominal radiation and the use of certain anti-neoplastic agents such as gemtuzumab ozogamicin within 3 months of conditioning also seemed to increase the risk of VSOS.

Endothelial injury is thought to lead to deposition of fibrinogen and factor VIII within the venular walls and liver sinusoids. The sinusoids become dilated and congested by erythrocytes. Progressive venular occlusion occurs and ultimately leads to widespread zonal liver disruption and centrilobular hemorrhagic necrosis.

Sinusoidal hemostasis leads to an increase in sinusoidal pressures, endothelial edema within intrahepatic venules, and cholestasis. Ultimately this can result in portal hypertension. There are associated hepatorenal abnormalities, and capillary leak, and ultimately there may be multisystem organ failure, encephalopathy, and even death.

Epidemiology

SOS occurs and 5-10% of recipients of conventional allogeneic stem cell transplant using myeloablative conditioning. It is more common after allogeneic transplant then after autologous stem cell transplant, though is not a manifestation of graft-versus-host disease. It is unusual in recipients of low-dose conditioning regimens.

Prognosis

The prognosis depends on the degree of liver injury and dysfunction in the presence of associated multisystem organ failure. Many patients with mild to moderate SOS will have spontaneous and complete recovery. Survival for patients with mild SOS is over 90% at day 100 from transplant and over 70% for patients with moderated SOS. However, severe SOS is associated with over 90% mortality by day 100 after transplant, often from multisystem organ failure.

(Results of a prospective, randomized phase I/II trial using debribrotide to treat VOD/SOS after allogeneic SCT. Defibrotide was effective in treating severe VOD, and a dose for future phase III trials was defined.)